Solid delta9-tetrahydrocannabinol (delta9-thc) compositions

ABSTRACT

The invention relates to a solid Δ9-THC composition containing Δ9-THC and a powder former and having a molar ratio of Δ9-THC to powder former to form a flowable Δ9-THC powder. The powder former is selected from the group consisting of adenine, aspartame, caffeine, lactose, mannitol, nicotinamide, β-nicotinamide adenine dinucleotide, pipecolic acid, saccharin, aspartic acid, glutamic acid, glutamine, histidine, leucine, methionine, phenylalanine, proline, serine, tryptophan, valine, Epigallocatechin Gallate (EGCG), 2-Hydroxypropyl-beta-cyclodextrin (HPbCD), and Trimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof. The invention also relates to methods of making a solid Δ9-THC composition of the invention. The Δ9-THC may be synthetic Δ9-THC or may be extracted Δ9-THC. The invention provides pharmaceutical or nutraceutical composition containing a solid Δ9-THC composition of the invention and a pharmaceutically- or nutraceutically-acceptable carrier where Δ9-THC is present in a pharmaceutically or nutraceutically effective amount. The invention also provides methods of treating a disease, disorder, or condition by administering to a patient in need thereof a therapeutically effective amount of a solid Δ9-THC composition. A solid Δ9-THC composition of the invention may also be incorporated into food and beverage products.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. patent application 63/053,205,filed Jul. 17, 2020; to U.S. patent application 63/154,151, filed Feb.26, 2021; and to U.S. patent application 63/154,153, filed Feb. 26,2021. The disclosure of each application is incorporated herein byreference.

BACKGROUND

Cannabis has been a traditional drug and remedy in many cultures and fora long time. Cannabis was used for the treatment of various disordersranging from asthma to migraine until the early 20th century. For anoverview of natural cannabinoid compounds see David T. Brown ed.,Cannabis, Hardwood Academic Publishers 1998, ISBN 90-5702-291-5.Tetrahydrocannabinol (THC), more specifically(−)-trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and its isomers, is thepsychoactive component in cannabis. Recently, though it is a controlledsubstance, Δ⁹-THC has found therapeutic use as an appetite stimulant andan antiemetic. An example of a marketed Δ⁹-THC product is Marinol®(generic name dronabinol). Currently, the Δ⁹-THC product is formulatedas a soft gelatin capsule for oral administration in which the drug isdissolved in an oil. The disadvantage is that in this formulation Δ⁹-THCis not stable. Consequently, it has to be stored at low temperatures (4°C.). Δ⁹-THC is chemically unstable to light, oxygen and heat. The lowstability of a compound and the need to store the pharmaceuticalformulation in the refrigerator is a serious drawback for apharmaceutical product. Therefore, there is a need for stableformulations of Δ⁹-THC, which can be stored, for example, at ambientconditions for prolonged times.

Furthermore, purified Δ⁹-THC is a thick, brown, viscous, resinousmaterial that has been compared to pine-tree sap and/or rubber cement.Accordingly, Δ⁹-THC is extremely difficult to formulate and is notreadily adapted for incorporation into standard dosage forms that aretypically available for other, solid pharmaceutical compounds. In lightof the difficulties associated with its formulation, it would bedesirable to have a method to obtain such a drug substance in a solid,powder state.

Accordingly, there is also a need to have Δ⁹-THC formulations thatcontain specific, known amounts of Δ⁹-THC and which may be used toprepare pharmaceutical compositions of Δ⁹-THC for therapeutic use.Flowable powders offer the possibility to develop other dosage forms,for example, dry powder formulations for pulmonary delivery and tabletsfor oral or sublingual administration. There is a need for solid Δ⁹-THCcompositions. This invention answers such needs.

SUMMARY OF THE INVENTION

The invention relates to a solid Δ⁹-THC composition comprising,consisting essentially of, or consisting of Δ⁹-THC and a powder formerhaving a molar ratio of Δ⁹-THC to powder former to form a flowableΔ⁹-THC powder and where the powder former is selected from the groupconsisting of adenine, aspartame, caffeine, lactose, mannitol,nicotinamide, β-nicotinamide adenine dinucleotide, pipecolic acid,saccharin, aspartic acid, glutamic acid, glutamine, histidine, leucine,methionine, phenylalanine, proline, serine, tryptophan, valine,Epigallocatechin Gallate (EGCG), 2-Hydroxypropyl-beta-cyclodextrin(HPbCD), and Trimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof.In some embodiments the molar ratio of Δ⁹-THC to powder former may rangefrom about 4:1 to about 1:4, from about 3:1 to about 1:3, from about 2:1to about 1:2 or may be about 1:1. In one solid Δ⁹-THC composition, thepowder former is aspartame. In another the powder former is caffeine.And in another the powder former is L-valine.

The invention also relates to methods of making a solid Δ⁹-THCcomposition comprising, consisting essentially of, or consisting of thestep of combining Δ⁹-THC with a powder former under conditions and in amolar ratio to form a flowable Δ⁹-THC powder, where the powder former isselected from the group consisting of adenine, aspartame, caffeine,lactose, mannitol, nicotinamide, β-nicotinamide adenine dinucleotide,pipecolic acid, saccharin, aspartic acid, glutamic acid, glutamine,histidine, leucine, methionine, phenylalanine, proline, serine,tryptophan, valine, Epigallocatechin Gallate (EGCG),2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof. One method ofmaking a solid Δ⁹-THC composition comprises the steps of dissolving theΔ⁹-THC and the powder former in a solvent system to form a solution, andremoving the solvent from the solution to yield a solid Δ⁹-THCcomposition. In a method or in a composition of the invention the Δ⁹-THCmay be synthetic Δ⁹-THC or may be extracted Δ⁹-THC.

The invention provides pharmaceutical or nutraceutical compositioncomprising, consisting essentially of, or consisting of a solid Δ⁹-THCcomposition of the invention and a pharmaceutically- ornutraceutically-acceptable carrier, wherein Δ⁹-THC is present in thecomposition in a pharmaceutically or nutraceutically effective amount.The invention also provides methods of treating a disease, disorder, orcondition comprising, consisting essentially of, or consisting of thestep of administering to a patient in need thereof a therapeuticallyeffective amount of a solid Δ⁹-THC composition according to theinvention or of administering to a patient in need thereof a therapeuticcomposition containing a solid Δ⁹-THC composition.

A solid Δ⁹-THC composition may also be incorporated into food (edibles)and beverage products.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/Adenine powder.

FIG. 2 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/Aspartame powder.

FIG. 3 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/Caffeine powder.

FIG. 4 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/Glutamine powder.

FIG. 5 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/Histidine powder.

FIG. 6 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/Lactose powder.

FIG. 7 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/D-Mannitol powder.

FIG. 8 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/Nicotinamide powder.

FIG. 9 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/L-Pipecolic Acid powder.

FIG. 10 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/Saccharin powder.

FIG. 11 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/L-Tryptophan powder.

FIG. 12 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:1 Δ⁹-THC/L-Valine powder.

FIG. 13 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/L-Aspartic Acid powder.

FIG. 14 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/L-Glutamic Acid powder.

FIG. 15 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/L-Leucine powder.

FIG. 16 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/L-Methionine powder.

FIG. 17 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/β-nicotinamide Adenine Dinucleotide powder.

FIG. 18 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:2 Δ⁹-THC/L-Phenylalanine powder.

FIG. 19 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/L-Proline powder.

FIG. 20 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/L-Serine powder.

FIG. 21 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/Aspartame 1:1 powder prepared by evaporation.

FIG. 22 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/Caffeine 1:1 powder prepared by evaporation.

FIG. 23 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/L-Pipecolic Acid 1:1 powder prepared by evaporation.

FIG. 24 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/Aspartame 1:1 powder prepared by physical mixing.

FIG. 25 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/Caffeine 1:1 powder prepared by physical mixing.

FIG. 26 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/Lactose 1:1 powder prepared by physical mixing.

FIG. 27 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/L-Pipecolic Acid 1:1 powder prepared by physical mixing.

FIG. 28 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 2:1 Δ⁹-THC/EGCG powder.

FIG. 29 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:2 Δ⁹-THC/L-glutamine powder.

FIG. 30 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/HPbCD 1:1 powder prepared by rotary evaporation.

FIG. 31 shows the X-ray powder diffraction (XRPD) pattern of aΔ⁹-THC/TOMBC 1:1 powder prepared by rotary evaporation.

FIG. 32 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:2 Δ⁹-THC/Aspartame powder.

FIG. 33 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/Aspartame powder.

FIG. 34 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 2:1 Δ⁹-THC/Aspartame powder.

FIG. 35 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 4:1 Δ⁹-THC/Aspartame powder.

FIG. 36 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:2 Δ⁹-THC/L-Valine powder.

FIG. 37 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/L-Valine powder.

FIG. 38 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 2:1 Δ⁹-THC/L-Valine powder.

FIG. 39 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 4:1 Δ⁹-THC/L-Valine powder.

FIG. 40 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:2 Δ⁹-THC/Caffeine powder.

FIG. 41 shows the X-ray powder diffraction (XRPD) pattern of afreeze-dried 1:4 Δ⁹-THC/Caffeine powder.

DESCRIPTION OF THE INVENTION Solid Δ⁹-THC Compositions

The invention relates to a solid Δ⁹-THC composition comprising,consisting essentially of, or consisting of Δ⁹-THC as a first componentand a powder former as a second component. In a solid Δ⁹-THC compositionof the invention the Δ⁹-THC and the powder former are present in a molarratio of Δ⁹-THC to powder former to form a flowable Δ⁹-THC powder. Aflowable powder is a solid composition of loose particulates that flowas a bulk property of the powder. In common terms, by way ofillustration, the powder may flow through an orifice (e.g., sand throughan hourglass) or may be poured (e.g., sugar from a packet). In someinstances, a flowable powder may have a static or triboelectric chargethat impacts its flow and may cause it to adhere to a surface.

In a solid Δ⁹-THC composition of the invention the powder former isselected from the group consisting of adenine, aspartame, caffeine,lactose, mannitol, nicotinamide, β-nicotinamide adenine dinucleotide,pipecolic acid, saccharin, aspartic acid, glutamic acid, glutamine,histidine, leucine, methionine, phenylalanine, proline, serine,tryptophan, valine, Epigallocatechin Gallate (EGCG),2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof. Each powderformer may be used individually in a solid Δ⁹-THC composition of theinvention. Combinations of two, three, four, five or more, up to amixture of all powder formers, may be used solid Δ⁹-THC composition ofthe invention.

The powder formers include the amino acids aspartic acid, glutamic acid,glutamine, histidine, leucine, methionine, phenylalanine, proline,serine, tryptophan and valine which may be L-amino acids, D-amino acidsor D,L-amino acids. The amino acid powder formers may be L-asparticacid, L-glutamic acid, L-glutamine, L-histidine, L-leucine,L-methionine, L-phenylalanine, L-proline, L-serine, L-tryptophan,L-valine and mixtures thereof. When the powder former is pipecolic acidit may be L-pipecolic acid, D-pipecolic acid or D,L-pipecolic acid.

A solid Δ⁹-THC composition of the invention has Δ⁹-THC and the powderformer combined in molar ratios of Δ⁹-THC to powder former which form aflowable Δ⁹-THC powder. Exemplary molar ratios of Δ⁹-THC to powderformer may range from about 4:1 to about 1:4, may range from about 3:1to about 1:3, may range from about 2:1 to about 1:2 or may be about 1:1.Solid Δ⁹-THC compositions of the invention are not limited to theseexemplary molar ratios. Different powder formers may have differentΔ⁹-THC to powder former molar ratios which yield a flowable Δ⁹-THCpowder.

One solid Δ⁹-THC composition comprises Δ⁹-THC and a powder former havinga molar ratio of Δ⁹-THC to powder former to form a flowable Δ⁹-THCpowder and wherein the powder former is selected from the groupconsisting of aspartic acid, glutamic acid, glutamine, histidine,leucine, methionine, phenylalanine, proline, serine, tryptophan, valineand mixtures thereof. Exemplary molar ratios of Δ⁹-THC to powder formermay range from about 4:1 to about 1:4, may range from about 3:1 to about1:3, may range from about 2:1 to about 1:2 or may be about 1:1.

A solid Δ⁹-THC composition of the invention comprises Δ⁹-THC andL-valine as the powder former and has a molar ratio of Δ⁹-THC to powderformer to form a flowable Δ⁹-THC powder. Exemplary molar ratios ofΔ⁹-THC to the L-valine powder former may range from about 4:1 to about1:4, may range from about 3:1 to about 1:3, may range from about 2:1 toabout 1:2 or may be about 1:1.

Another solid Δ⁹-THC composition of the invention comprises Δ⁹-THC andaspartame as the powder former and has a molar ratio of Δ⁹-THC to powderformer to form a flowable Δ⁹-THC powder. Exemplary molar ratio of Δ⁹-THCto the aspartame powder former may range from about 4:1 to about 1:4,may range from about 3:1 to about 1:3, may range from about 2:1 to about1:2 or may be about 1:1.

One other solid Δ⁹-THC composition of the invention comprises Δ⁹-THC andcaffeine as the powder former and has a molar ratio of Δ⁹-THC to powderformer to form a flowable Δ⁹-THC powder. Exemplary molar ratios ofΔ⁹-THC to the caffeine powder former may range from about 1:1 to about1:4, may range from about 1:1 to about 1:3, may range from about 1:1 toabout 1:2 or may be about 1:1.

Methods of Making Solid Δ⁹-THC Compositions

A solid Δ⁹-THC composition of the invention may be made by a variety ofmethods known in the art which combine Δ⁹-THC and a powder formeraccording to the invention. For example, a solid Δ⁹-THC composition maybe made by lyophilizing (freeze drying) a solution of Δ⁹-THC and apowder former or by slow or rotary evaporation of the solvent from thesolution. A solid Δ⁹-THC composition of the invention may also be madeby simple mixing of Δ⁹-THC and a powder former. Accordingly, theinvention relates to a method of making a solid Δ⁹-THC composition bycombining Δ⁹-THC with a powder former under conditions to form aflowable Δ⁹-THC powder. The Δ⁹-THC and the powder former are combined ina molar ratio of Δ⁹-THC to powder former which form a flowable Δ⁹-THCpowder. Exemplary molar ratios have been discussed above and are shownin the examples below.

The invention relates to a method of making a solid Δ⁹-THC compositionby dissolving Δ⁹-THC and a powder former in a solvent system to form asolution. If the Δ⁹-THC and powder former are first dissolved separatelythen the solutions may be combined to form a solution containing bothΔ⁹-THC and the powder former. The Δ⁹-THC and the powder former arepresent in the solution in a molar ratio of Δ⁹-THC to powder formerwhich form a flowable Δ⁹-THC powder once the solvent is removed. Thesolvent is then removed from the solution, for example by lyophilizationor by evaporation, to yield a flowable powder. Solvents that dissolveboth the Δ⁹-THC and the powder former may be used as well as mixtures ofsolvents such that the Δ⁹-THC and powder former remain in solution.Suitable solvents include, for example, dioxane, dimtheylsulfoxide(DMSO), N,N-dimethylformamide (DMF), acetonitrile, ethyl acetate, andC₂-C₄ alcohols (ethanol, propanol and the like). Water may be used butshould be miscible with the solvent used to dissolve the Δ⁹-THC and notso much as to cause precipitation of the Δ⁹-THC from the solution.

A Δ⁹-THC powder composition of the invention may also be made bycombining synthetic Δ⁹-THC and a powder former as just described in amolar ratio of Δ⁹-THC to powder former to form a flowable Δ⁹-THC powder.Alternatively, a Δ⁹-THC powder composition of the invention may also bemade by combining extracted Δ⁹-THC and a powder former as just describedin a molar ratio of Δ⁹-THC to powder former to form a flowable Δ⁹-THCpowder.

In one method of the invention (+)-p-Menth-2-ene-1,8-diol is reactedwith olivetol to prepare synthetic delta-9-tetrahydrocannibinol(Δ⁹-THC). See US 2007/0287843 which is incorporated by reference.(+)-p-Menth-2-ene-1,8-diol may be prepared from a reaction mixtureincluding 2-carene epoxide, a solvent in which(+)-p-Menth-2-ene-1,8-diol is insoluble, water, and an acid catalyst.Id. at ¶ [0013]. (+)-p-Menth-2-ene-1,8-diol can also be prepared bymixing 2-carene epoxide and 3-carene epoxide, a solvent in which(+)-p-Menth-2-ene-1,8-diol is insoluble, water, and an acid catalyst.Id. at ¶ [0014]. Therefore, Δ⁹-THC can be synthesized when cycliccompounds prepared from 2-carene, or cyclic compounds prepared frommixtures of 2-carene and 3-carene, are reacted with unsubstitutedresorcinol or a substituted resorcinol (such as olivetol). Id. at ¶[0015]. The resulting synthetic Δ⁹-THC is then combined with a powderformer selected from the group consisting of adenine, aspartame,caffeine, glutamine, histidine, lactose, mannitol, nicotinamide,pipecolic acid, saccharin, tryptophan, valine, Epigallocatechin Gallate(EGCG), 2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof using a methodsuch as those described above. For example, by combination in a solventsystem to form a solution where the solvent is then removed from thesolution to yield a THC powder.

Another method of the invention prepares synthetic Δ⁹-THC in a “one-pot”condensation and sulfonylation reaction sequence which first produces acrude Δ⁹-THC aryl sulfonate ester, which is then hydrolyzed to producesynthetic Δ⁹-THC. See WO 2009/099868 which is incorporated by reference.Δ⁹-THC can be synthesized by condensing a substituted resorcinolcompound in the presence of an acid catalyst and a non-alkalinedehydrating agent. Id. at ¶ [0017]. After completion of the condensationreaction, the reaction mixture is sulfonated by treating the reactionmixture with an aryl sulfonyl halide in the presence of a base toproduce an aryl sulfonate. Id. at ¶ [0019]. The isolated aryl sulfonateis then hydrolyzed to form synthetic Δ⁹-THC. Id. at ¶ [0020]. Theresulting synthetic Δ⁹-THC is then combined with a powder formerselected from the group consisting of adenine, aspartame, caffeine,glutamine, histidine, lactose, mannitol, nicotinamide, pipecolic acid,saccharin, tryptophan, valine, Epigallocatechin Gallate (EGCG),2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof using a methodsuch as those described above. For example, by combination in a solventsystem to form a solution where the solvent is then removed from thesolution to yield a THC powder.

In one method of the invention synthetic Δ⁹-THC is prepared by treatinga first intermediate compound with an organoaluminum-based Lewis acidcatalyst. See WO 2007/041167, which is incorporated by reference. Thefirst intermediate compound is a compound of formula I:

where:R₁ is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;R₂ is H, OH, protected hydroxyl, substituted or unsubstituted alkyl,alkenyl, alkynyl, acyl, aryl, or heteroaryl;R₃ is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;andR₄ is H, substituted or unsubstituted alkyl, silyl, hetero-substitutedor unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, orarylphosphoryl. Id. pg. 2 line 29-pg. 3 line 9. The resulting syntheticΔ⁹-THC is then combined with a powder former selected from the groupconsisting of adenine, aspartame, caffeine, glutamine, histidine,lactose, mannitol, nicotinamide, pipecolic acid, saccharin, tryptophan,valine, Epigallocatechin Gallate (EGCG),2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof using a methodsuch as those described above. For example, by combination in a solventsystem to form a solution where the solvent is then removed from thesolution to yield a Δ⁹-THC powder.

In another method of the invention, 6,12-dihydro-6-hydroxy-cannabidiolis subjected to ring condensation to prepare synthetic Δ⁹-THC. See EP0494665, which is incorporated by reference. The ring condensation isperformed in a solvent selected from the group consisting ofhydrocarbons, aromatic hydrocarbons, and chlorinated hydrocarbons. Id.at claim 9. The resulting synthetic Δ⁹-THC is then combined with apowder former selected from the group consisting of adenine, aspartame,caffeine, glutamine, histidine, lactose, mannitol, nicotinamide,pipecolic acid, saccharin, tryptophan, valine, Epigallocatechin Gallate(EGCG), 2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof using a methodsuch as those described above. For example, by combination in a solventsystem to form a solution where the solvent is then removed from thesolution to yield a Δ⁹-THC powder.

In another method of the invention, cannabidiol (CBD) is present in anorganic solvent and cyclized to prepare synthetic Δ⁹-THC in the presenceof a molecular sieve while being heated. See U.S. Pat. No. 8,324,408,which is incorporated by reference. The CBD dissolved in an organicsolvent is contacted with the molecular sieve while being boiled underreflex. Id. at claim 2. The resulting synthetic Δ⁹-THC is then combinedwith a powder former selected from the group consisting of adenine,aspartame, caffeine, glutamine, histidine, lactose, mannitol,nicotinamide, pipecolic acid, saccharin, tryptophan, valine,Epigallocatechin Gallate (EGCG), 2-Hydroxypropyl-beta-cyclodextrin(HPbCD), and Trimethyl-beta-cyclodextrin (TOMBC) and mixtures thereofusing a method such as those described above. For example, bycombination in a solvent system to form a solution where the solvent isthen removed from the solution to yield a Δ⁹-THC powder.

In another method of the invention, synthetic Δ⁹-THC is prepared fromCBD. See WO 2002/070506, which is incorporated by reference. A catalystis added to a reaction mixture comprising CBD in an organic solventunder a nitrogen atmosphere. Id. at 3. NaHCO₃ is added to the reactionmixture and stirred. Id. at 4. The mixture is allowed to separate intoan aqueous phase and an organic phase. Id. The organic phase is removedand the Δ⁹-THC is eluted from the organic phase. Id. The resultingsynthetic Δ⁹-THC is then combined with a powder former selected from thegroup consisting of adenine, aspartame, caffeine, glutamine, histidine,lactose, mannitol, nicotinamide, pipecolic acid, saccharin, tryptophan,valine, Epigallocatechin Gallate (EGCG),2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) and mixtures thereof using a methodsuch as those described above. For example, by combination in a solventsystem to form a solution where the solvent is then removed from thesolution to yield a Δ⁹-THC powder.

In one method of the invention Δ⁹-THC is extracted from plant materialwith a non-polar solvent followed by vacuum distillation andchromatography. See U.S. Pat. No. 6,365,416 which is incorporated byreference. The Cannabis plant material is extracted with a non-polarorganic solvent to form an extract. Id. at claim 1. The solvent isremoved from the extract resulting in an extract residue. Id. Theextract residue is subjected to a first low-pressure flash distillationwhere the first distillate contains Δ⁹-THC. Id. The first distillate canbe subjected to a second low pressure flash distillation to produce asecond distillate containing Δ⁹-THC. Id. The first and second distillateare subjected to column chromatography, normal HPLC, or reversed HPLC toresult in a product containing Δ⁹-THC. Id. The extracted THC is thencombined with a powder former selected from the group consisting ofadenine, aspartame, caffeine, glutamine, histidine, lactose, mannitol,nicotinamide, pipecolic acid, saccharin, tryptophan, valine,Epigallocatechin Gallate (EGCG), 2-Hydroxypropyl-beta-cyclodextrin(HPbCD), and Trimethyl-beta-cyclodextrin (TOMBC) and mixtures thereofusing a method such as those described above. For example, bycombination in a solvent system to form a solution where the solvent isthen removed from the solution to yield a Δ⁹-THC powder.

In another method of the invention, Δ⁹-THC is extracted from cannabisplants using supercritical fluid. See, e.g., US 2003/0050334 and WO2020/102898 which are both incorporated by reference. The plant issubjected to a supercritical fluid, preferably liquid CO₂, either aloneor in combination with other cosolvents to extract the Δ⁹-THC. See US2003/0050334 at ¶ [0053]. The extraction occurs at a temperature >65° C.for selectively extracting Δ⁹-THC over CBD from the plant material. SeeWO 2020/102898 at claim 1. The extracted Δ⁹-THC is then combined with apowder former selected from the group consisting of adenine, aspartame,caffeine, glutamine, histidine, lactose, mannitol, nicotinamide,pipecolic acid, saccharin, tryptophan, valine, Epigallocatechin Gallate(EGCG), 2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) mixtures thereof using a method suchas those described above. For example, by combination in a solventsystem to form a solution where the solvent is then removed from thesolution to yield a Δ⁹-THC powder.

In another method of the invention, Δ⁹-THC is extracted from a cannabisplant by irradiating microwaves to a reaction mixture comprising aCBD-comprising sample, a Lewis acid, and a solvent in an airtightcontainer. See US 2021/0002247 which is incorporated by reference. Theextracted Δ⁹-THC is then combined with a powder former selected from thegroup consisting of adenine, aspartame, caffeine, glutamine, histidine,lactose, mannitol, nicotinamide, pipecolic acid, saccharin, tryptophan,valine, Epigallocatechin Gallate (EGCG),2-Hydroxypropyl-beta-cyclodextrin (HPbCD), andTrimethyl-beta-cyclodextrin (TOMBC) mixtures thereof using a method suchas those described above. For example, by combination in a solventsystem to form a solution where the solvent is then removed from thesolution to yield a Δ⁹-THC powder.

Uses of Solid Δ⁹-THC Compositions

As discussed above Δ⁹-THC is known in the art to be useful in thetreatment of various diseases, disorders, and conditions. The solidΔ⁹-THC compositions of the invention, and pharmaceutical compositionscontaining them may then also be used to treat such diseases, disorders,and conditions. The diseases, disorders or conditions which may betreated with a solid Δ⁹-THC composition of the invention include, butare not limited to: pain (including but not limited to acute pain;chronic pain; neuropathic pain and cancer pain), neurodegenerativedisease (including but not limited to Alzheimer's disease; Parkinson'sdisease; amyotrophic lateral sclerosis; Huntington's disease; multiplesclerosis; frontotemporal dementia; prion disease; Lewy body dementia;progressive supranuclear palsy; vascular dementia; normal pressurehydrocephalus; traumatic spinal cord injury; HIV dementia; alcoholinduced neurotoxicity; Down's syndrome; epilepsy or any other relatedneurological or psychiatric neurodegenerative disease), inflammatory orautoimmune disease, fibrosis, cancer, nausea and vomiting, diabetes,adiposity and metabolic syndrome.

Accordingly, the invention relates to the method of treating such adisease, disorder, or condition comprising, consisting essentially of,or consisting of the step of administering to a patient in need thereofa therapeutically effective amount of a solid Δ⁹-THC composition of theinvention or of administering to a patient in need thereof a therapeuticcomposition containing a solid Δ⁹-THC composition of the invention.

The term “treatment” or “treating” means any treatment of a disease,disorder or condition in a mammal, including: preventing or protectingagainst the disease, disorder or condition, that is, causing theclinical symptoms not to develop; inhibiting the disease, disorder orcondition, that is, arresting or suppressing the development of clinicalsymptoms; and/or relieving the disease, disorder or condition (includingthe relief of discomfort associated with the condition or disorder),that is, causing the regression of clinical symptoms. It will beunderstood by those skilled in the art that in human medicine, it is notalways possible to distinguish between “preventing” and “suppressing”since the ultimate inductive event or events may be unknown, latent, orthe patient is not ascertained until well after the occurrence of theevent or events. Therefore, as used herein the term “prophylaxis” isintended as an element of “treatment” to encompass both “preventing” and“suppressing” the disease, disorder or condition. The term “protection”is meant to include “prophylaxis.”

Another aspect of the invention relates to the use of a solid Δ⁹-THCcomposition of the invention in the treatment of diseases, disorders andconditions discussed above. Accordingly, the invention further relatesto the manufacture of a medicament for use in the treatment of suchdiseases, disorders and conditions.

Compositions Containing Solid Δ⁹-THC Compositions

The invention relates to a pharmaceutical or nutraceutical compositioncontaining a solid Δ⁹-THC composition of the invention and apharmaceutically- or nutraceutically-acceptable carrier. Apharmaceutical or nutraceutical composition includes vitamincompositions. The solid Δ⁹-THC composition may be present as a flowablepowder and may be mixed with the carrier. Δ⁹-THC is present in thecomposition in a pharmaceutically- or nutraceutically-effective amount.As mentioned above, these pharmaceutical compositions aretherapeutically useful to treat or prevent disorders such as thosediscussed above. Such a composition of the invention may be a soliddosage form or a solution made with a solid Δ⁹-THC composition of theinvention.

A composition of the invention may be in any pharmaceutical ornutraceutical form which contains a solid Δ⁹-THC composition accordingto the invention. The composition may be, for example, a tablet, acapsule, a consumable formulation, an injectable composition, a topicalcomposition, an inhalable composition or a transdermal composition.

The compositions generally contain, for example, about 0.1% to about99.9% by weight of a solid Δ⁹-THC composition of the invention, forexample, about 0.5% to about 99% by weight of a solid Δ⁹-THC compositionof the invention and, for example, 99.5% to 0.5% by weight of at leastone suitable pharmaceutical excipient or solvent. In one embodiment, thecomposition may be between about 5% and about 75% by weight of a solidΔ⁹-THC composition of the invention with the rest being at least onesuitable pharmaceutical excipient, solvent or at least one otheradjuvant, as discussed below.

A “therapeutically effective amount of Δ⁹-THC according to theinvention” is that which correlates to a therapeutic effect and may forexample, be about 5 mg about 2,000 mg, about 50 mg about 1500 mg, about100 mg about 1000 mg, about 250 mg about 750 mg, or about 500 mg. Theactual amount required for treatment of any particular disease, disorderor condition for any particular patient may depend upon a variety offactors including, for example, the particular disease, disorder orcondition being treated; the disease state being treated and itsseverity; the specific pharmaceutical composition employed; the age,body weight, general health, sex and diet of the patient; the mode ofadministration; the time of administration; the route of administration;and the rate of excretion; the duration of the treatment; any drugs usedin combination or coincidental with the specific compound employed; andother such factors well known in the medical arts. These factors arediscussed in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics”, Tenth Edition, A. Gilman, J. Hardman and L. Limbird,eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein byreference.

Depending on the type of composition, the pharmaceutically-acceptable ornutraceutically-acceptable carrier may be chosen from any one or acombination of carriers known in the art. The choice of carrier dependsupon the pharmaceutical or nutraceutical form and the desired method ofadministration to be used. The carrier should not substantially alterthe solid Δ⁹-THC composition, for example, such that the solid Δ⁹-THCcomposition becomes tacky or the Δ⁹-THC component becomes oily. Norshould the carrier be otherwise incompatible with a solid Δ⁹-THCcomposition used, such as by producing any undesirable biological effector otherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutical or nutraceutical composition.

The pharmaceutical or nutraceutical compositions of the invention may beprepared by methods known in the formulation art, for example, seeRemington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company,Easton, Pa., 1990), which is incorporated herein by reference. In asolid dosage form, a solid Δ⁹-THC composition of the invention may beadmixed with at least one pharmaceutically-acceptable ornutraceutically-acceptable excipient such as, for example, sodiumcitrate or dicalcium phosphate or (a) fillers or extenders, such as, forexample, starches, lactose, sucrose, glucose, mannitol, and silicicacid, (b) binders, such as, for example, cellulose derivatives, starch,alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c)humectants, such as, for example, glycerol, (d) disintegrating agents,such as, for example, agar-agar, calcium carbonate, potato or tapiocastarch, alginic acid, croscarmellose sodium, complex silicates, andsodium carbonate, (e) solution retarders, such as, for example,paraffin, (f) absorption accelerators, such as, for example, quaternaryammonium compounds, (g) wetting agents, such as, for example, cetylalcohol, and glycerol monostearate, magnesium stearate and the like (h)adsorbents, such as, for example, kaolin and bentonite, and (i)lubricants, such as, for example, talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, or mixturesthereof. In the case of capsules, tablets, and pills, the dosage formsmay also comprise buffering agents.

Pharmaceutically-acceptable and nutraceutically-acceptable adjuvantsknown in the pharmaceutical and nutraceutical formulation art may alsobe used in the pharmaceutical or nutraceutical compositions of theinvention. These include, but are not limited to, preserving, wetting,suspending, sweetening, flavoring, perfuming, emulsifying, anddispensing agents. Prevention of the action of microorganisms may beensured by inclusion of various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, and the like. Itmay also be desirable to include isotonic agents, for example, sugars,sodium chloride, and the like. If desired, a pharmaceutical compositionof the invention may also contain minor amounts of auxiliary substancessuch as wetting or emulsifying agents, pH buffering agents,antioxidants, and the like, such as, for example, citric acid, sorbitanmonolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

Solid dosage forms as described above may be prepared with coatings andshells, such as enteric coatings and others, as is known in thepharmaceutical or nutraceutical art. They may contain pacifying agentsand can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Non-limiting examples of embedded compositions that maybe used are polymeric substances and waxes. The active compounds mayalso be in microencapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.

Suspensions, in addition to the active compounds, may contain suspendingagents, such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures of these substances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat may be prepared by mixing a solid Δ⁹-THC composition of theinvention with, for example, suitable non-irritating excipients orcarriers such as cocoa butter, polyethyleneglycol or a suppository wax,which may be solid at ordinary temperatures but may be liquid at bodytemperature and, therefore, melt while in a suitable body cavity andrelease the active component therein.

Compositions suitable for topical administration include liquid orsemi-liquid preparations such as liniments, lotions, gels, applicants,oil-in-water or water-in-oil emulsions such as creams, ointments, pastesor foams; or solutions or suspensions such as drops, as is known in theart. Compositions of the invention may be intended for topicaladministration, in which case the carrier may suitably comprise asolution, emulsion, ointment or gel base. The carrier or base, forexample, may comprise one or more of the following: petrolatum, lanolin,polyethylene glycols, bee wax, mineral oil, diluents such as water andalcohol, and emulsifiers and stabilizers. Thickening agents may bepresent in a pharmaceutical composition for topical administration. Ifintended for transdermal administration, the composition may include atransdermal patch or iontophoresis device. Topical formulations maycontain a concentration of the compound of the invention from about 0.1to about 10% w/v (weight per unit volume).

In addition to the topical method of administration described above,there are various methods of administering the active a solid Δ⁹-THCcomposition of the invention topically to the lung. One such means couldinvolve a dry powder inhaler formulation of respirable particlescomprised of a solid Δ⁹-THC composition of the invention, which thepatient being treated inhales. It is common for a dry powder formulationto include carrier particles, to which the solid Δ⁹-THC compositionparticles can adhere to. The carrier particles may be of any acceptablepharmacologically inert material or combination of materials. Forexample, the carrier particles may be composed of one or more materialsselected from sugar alcohols; polyols, for example sorbitol, mannitol orxylitol, and crystalline sugars, including monosaccharides anddisaccharides; inorganic salts such as sodium chloride and calciumcarbonate; organic salts such as sodium lactate; and other organiccompounds such as urea, polysaccharides, for example cyclodextrins anddextrins. The carrier particles may be a crystalline sugar, for example,a monosaccharide such as glucose or arabinose, or a disaccharide such asmaltose, saccharose, dextrose or lactose.

In addition to the topical method of administration described above,there are various methods of administering the active a solid Δ⁹-THCcomposition of the invention systemically by such methods. One suchmeans would involve an aerosol suspension of respirable particlescomprised of a solid Δ⁹-THC composition of the invention, which thepatient being treated inhales. A solid Δ⁹-THC composition would beabsorbed into the bloodstream via the lungs in a pharmaceuticallyeffective amount. The respirable particles can be liquid or solid, witha particle size sufficiently small to pass through the mouth and larynxupon inhalation.

Because the solid Δ⁹-THC composition may be maintained duringpreparation, solid dosage forms are one embodiment of the pharmaceuticalcomposition of the invention. Dosage forms for oral administration,which includes capsules, tablets, pills, powders, granules, andsuspensions may be used. Dosage forms for pulmonary administration,which includes metered dose inhaler, dry powder inhaler or aerosolformulations may be used. In such solid dosage forms, the activecompound may be mixed with at least one inert,pharmaceutically-acceptable or nutraceutically-acceptable excipient(also known as a pharmaceutically-acceptable ornutraceutically-acceptable carrier).

Edible Compositions

A solid Δ⁹-THC composition of the invention may also be incorporatedinto an edible composition such as food products and beverages. The foodproducts may be prepared food products such as cakes, candy, breads,etc. or mixes used to prepare such products. The food product may alsobe a tea or a coffee used to prepare a tea or coffee beverage. Thebeverage product may be a ready-to-drink beverage such as soda, tea,coffee, juices, sports drinks, beer, etc. The food product or beveragemay be for human or animal consumption.

EXAMPLES X-Ray Powder Diffraction (XRPD) for Examples 1-3 and 6

A Rigaku Smart-Lab X-ray diffraction system was configured forreflection BraggBrentano geometry using a line source X-ray beam. Thex-ray source is a Cu Long Fine Focus tube that was operated at 40 kV and44 mA. That source provides an incident beam profile at the sample thatchanges from a narrow line at high angles to a broad rectangle at lowangles. Beam conditioning slits are used on the line X-ray source toensure that the maximum beam size is less than 10 mm both along the lineand normal to the line. The Bragg-Brentano geometry is a para-focusinggeometry controlled by passive divergence and receiving slits with thesample itself acting as the focusing component for the optics. Theinherent resolution of Bragg-Brentano geometry is governed in part bythe diffractometer radius and the width of the receiving slit used.Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1°2θ or less. The axial divergence of the X-ray beam is controlled by5.0-degree Soller slits in both the incident and diffracted beam paths.Powder samples were prepared in a low background Si holder using lightmanual pressure to keep the sample surfaces flat and level with thereference surface of the sample holder. Each sample was analyzed from 2to 40 °2θ using a continuous scan of 6 °2θ per minute with an effectivestep size of 0.02° 20.

X-ray Powder Diffraction (XRPD) for Examples 4 and 5

XRPD patterns were also collected with a PANalytical X'Pert PRO MPD or aPANalytical Empyrean diffractometer using an incident beam of Curadiation produced using an Optix long, fine-focus source. Anelliptically graded multilayer mirror was used to focus Cu Kα X-raysthrough the specimen and onto the detector. Prior to the analysis, asilicon specimen (NIST SRM 640f) was analyzed to verify the observedposition of the Si 111 peak is consistent with the NIST-certifiedposition. A specimen of the sample was sandwiched between 3-μm-thickfilms and analyzed in transmission geometry. A beam-stop, shortantiscatter extension, and antiscatter knife edge were used to minimizethe background generated by air. Soller slits for the incident anddiffracted beams were used to minimize broadening from axial divergence.Diffraction patterns were collected using a scanning position-sensitivedetector (X'Celerator) located 240 mm from the specimen and DataCollector software v. 5.5.

Example 1: Solid Δ⁹-THC Compositions by Freeze-Drying (Lyophilization)

A commercially available Δ⁹-THC-acetonitrile solution (Cayman Chemical),approximately 50 mg Δ⁹-THC per mL, was used. The actual concentrationwas determined gravimetrically by taring a vial and recording itsweight, adding 1 mL of solution, evaporating the solution, vacuum dryingthe sample at room temperature for 12 hours and reweighing the vial. Theactual concentration was determined to be 51 mg/mL. Into 1 dram vials,300 μl of the Δ⁹-THC acetonitrile solution was dispensed and allowed toevaporate at room temperature resulting in each vial containing ca. 15.3mg of Δ⁹-THC.

Δ⁹-THC (ca. 15.3 mg) was dissolved in dioxane (3 mL solvent used) andtransferred into a 25 mL round bottom flask. The powder former (amountbased on 1:1, 1:2 or 1:4 molar Δ⁹-THC:powder former ratio) was dissolvedin H₂O (2 mL) and, if needed, dioxane (2 mL) was added to form asolution. The powder former solution was added to the Δ⁹-THC solution inthe round bottom flask. The round bottom flask was then submerged in adry ice/acetone bath or liquid nitrogen to freeze the solution whilecontinuously rotating the flask by hand to maximize surface area andform an even, thin layer around the flask. Once frozen, the round bottomflask was attached to a LabConco lyophilizer with an Edwards RV8 vacuumpump pre-equilibrated at ˜−50° C. Samples were left overnight (18 hrs)and removed the next day.

Δ⁹-THC and several powder formers were lyophilized using the describedprocedure to determine if a flowable powder would result. Experimentsusing L-asparagine, L-leucine, and L-aspartic add required heating at˜45° C. overnight to obtain a clear solution. In these cases, thesolution of powder former was added to the Δ⁹-THC solution while stillhot. To minimize the risk of precipitation, the round bottom flask wasquickly submerged in either a dry ice/acetone bath or liquid nitrogen tofreeze the solution.

Lyophilizing Δ⁹-THC according to the same procedure, without a powderformer, from dioxane alone resulted in a gel and from dioxane/water(˜75/25 by volume) resulted in a tacky gel. Proton (¹H) NMR analysis ofthe flowable powders showed the THC present to be Δ⁹-THC. A sampling ofthe Δ⁹-THC:powder former flowable powders were stored at sub-ambienttemperatures (˜−18° C.) for 21-30 days and observed to see if a flowablepowder remained. A sampling of the Δ⁹-THC flowable powders were thenleft at ambient temperature and again observed to see if a flowablepowder remained. These results are also shown in Table 1 and Table 2.

TABLE 1 Δ⁹-THC: Flowable Powder solids- Flowable solids- former Flowablesub-ambient ambient temp. Powder former ratio powder temp. (minimum 30days) Adenine 1:1 Yes Yes Yes-Dark beige color Aspartame 1:1 Yes YesYes-Light beige color Caffeine 1:1 Yes Yes Yes-Light beige colorGlutamine 1:1 Yes Yes Yes-Light beige color Histidine 1:1 Yes YesYes-Dark beige color Lactose 1:1 Yes Yes Yes-Light beige colorD-Mannitol 1:1 Yes Yes Yes-Dark beige color Nicotinamide 1:1 Yes YesNo-Red/brown tacky solid L-Pipecolic acid 1:1 Yes Yes-light beigeYes-Brown color Saccharin 1:1 Yes Yes Yes-Dark beige color L-Tryptophan1:1 Yes Yes Yes-Light beige color L-Valine 1:1 Yes Yes Yes-Light beigecolor L-Arginine 1:1 No-Gel/tacky solid L-Ascorbic acid 1:1 No-Tackysolid D-Fructose 1:1 No-Tacky solid Glycine 1:1 No-Tacky solid Glycolicacid 1:1 No-Tacky gel L-Lactic acid 1:1 No-Gel Nicotinic acid 1:1 No-GelPropyl gallate 1:1 No-Gel Salicylic acid 1:1 No-Gel Sucralose 1:1No-Tacky solid Sucrose 1:1 No-Tacky solid Urea 1:1 No-Tacky solidVanillic acid 1:1 No-Gummy solid Vanillin 1:1 No-Gel

TABLE 2 Δ9-THC: Powder former Flowable solids- Powder former ratioambient temp. L-Aspartic acid 1:4 Yes-Tan color L-Glutamic acid 1:4Yes-Yellow and white color L-Leucine 1:4 Yes-Yellow and white colorL-Methionine 1:4 Yes-Yellow and white color L-Phenylalanine 1:2Yes-White color L-Proline 1:4 Yes-Light orange color L-Serine 1:4Yes-Yellow and white color β-Nicotinamide 1:4 Yes-White color adeninedinucleotide L-Alanine 1:2 No-Tacky L-Asparagine 1:4 No-Tacky yellowcolor L-Lysine 1:2 No-Tacky gel L-Lysine 1:4 No-Tacky L-Proline 1:2No-Gel L-Threonine 1:4 No-Tacky β-nicotinamide mononucleotide 1:1No-Tacky Nicotinamide riboside chloride 1:4 No-Tacky gel

The flowable powders were characterized using a Rigaku Smart-Lab X-raydiffraction system and their X-ray powder diffraction (XRPD) patternsare shown in FIGS. 1-20. The Δ⁹-THC/Aspartame powder (FIG. 2),Δ⁹-THC/lactose powder (FIG. 6) and Δ⁹-THC/β-nicotinamide AdenineDinucleotide powder (FIG. 17) showed only an amorphous halo. The XRPDpatterns for each powder sample showed the presence of some powderformer and an amorphous halo.

Example 2: Solid Δ⁹-THC Compositions by Evaporation

Δ⁹-THC (ca. 15.3 mg, prepared as in Example 1) was dissolved in methanol(MeOH) (1 mL). A powder former (amount based on a 1:1 Δ⁹-THC:powderformer molar ratio) was added to the solution. If needed, additionalMeOH (1-3 mL) was added until solids dissolved completely. The vial wasleft uncapped for fast evaporation (FE) at ambient temperature. Thepowder formers used were aspartame, caffeine, histidine, lactose andL-pipecolic acid. The Δ⁹-THC/histidine mixture resulted in a gel afterevaporation. The other Δ⁹-THC/powder former mixtures were flowablepowders and remained flowable powders when left at ambient temperature.The XRPD patterns were obtained for the Δ⁹-THC/aspartame powder (FIG.21), Δ⁹-THC/caffeine powder (FIG. 22), and Δ⁹-THC/L-pipecolic acidpowder (FIG. 23). Each XRPD pattern showed the presence of somecrystalline powder former and an amorphous halo.

Example 3: Solid Δ⁹-THC Compositions by Physical Mixing

Δ⁹-THC (ca. 15.3 mg, prepared as in Example 1) and a powder former(amount based on 1:1 Δ⁹-THC:powder former molar ratio) were placed in a1 dram vial. The solids were mixed with a glass stir rod and metalspatula. The powder formers used were aspartame, caffeine, histidine,lactose and L-pipecolic acid. The resulting material was a powder. Theresulting materials were flowable powders and remained flowable powderswhen left at ambient temperature. The Δ⁹-THC/histidine mixture resultedin a tacky solid. The XRPD patterns were obtained for theΔ⁹-THC/aspartame powder (FIG. 24), the Δ⁹-THC/caffeine powder (FIG. 25),the Δ⁹-THC/lactose powder (FIG. 26), and the Δ⁹-THC/L-pipecolic acidpowder (FIG. 27). The XRPD patterns showed the presence of somecrystalline powder former and an amorphous halo.

Example 4: Solid Δ⁹-THC Compositions by Freeze-Drying (Lyophilization)

One capsule of Teavigo (Healthy Origins, 94% epigallocatechin gallate,EGCG) was emptied into a vial (net weight 207.7 mg; epigallocatechingallate content 195.2 mg). Water (1 mL) was added and the mixture wasstirred for approximately 30 minutes, affording a thick pink suspension.The suspension was filtered through a 0.2 μm nylon filter into a cleanvial, resulting in a clear pink solution. Epigallocatechin gallatecontent was not confirmed in the solution.

A portion of the epigallocatechin gallate aqueous solution (374 μL) wascombined with a solution of Δ⁹-THC in acetonitrile (1 mL of 50 mg/mLsolution, Cayman Chemicals), affording a clear, slightly pinkish-brownsolution. The solution was stirred at ambient temperature for 1 day andthen evaporated from a vial covered with perforated foil in a jar undernitrogen gas flow. A clear, brown, sticky oil resulted. Tert-butanol (1mL) and water (200 μL) were added to the oil with sonication, giving aclear orange solution. The solution was frozen in a thin layer on thewalls of the vial by rotating in a bath of dry ice and isopropanol, andthe vial was placed in a jar and attached to a Labconco FreeZone 2.5Liter −84° C. Benchtop Freeze Dryer at −87.1° C. and 0.159 torr. Afterone day, the sample was removed and free-flowing, fluffy, light pink,non-birefringent solids were observed. The XRPD pattern was obtained forthe 2:1 Δ⁹-THC/EGCG powder showing 2 amorphous halos (FIG. 28).

A solution of Δ⁹-THC in acetonitrile (1 mL of 50 mg/mL solution, CaymanChemicals) was added to a clean vial, stored in a freezer forapproximately 1 month, and evaporated under a stream of nitrogen gas,forming a brown oil. The oil was dissolved in tert-butanol (2 mL) withsonication. Two molar equivalents of L-glutamine (45.8 mg,Sigma-Aldrich) were dissolved in water (2 mL) with sonication. TheL-glutamine solution was added to the Δ⁹-THC solution with stirring, andprecipitation was observed. Additional water (2 mL) and tert-butanol (2mL) were added, affording a clear solution. The solution was frozen in athin layer on the walls of a flask by rotating in a bath of dry ice andisopropanol, and the flask was placed in a jar and attached to aLabconco FreeZone 2.5 Liter −84° C. Benchtop Freeze Dryer at −86.9° C.and ˜0.2 torr. After one day, the sample was removed and free-flowing,fluffy, very light purple, non-birefringent solids were observed. TheXRPD pattern of the 2:1 Δ⁹-THC/L-glutamine powder showed the presence ofsome crystalline powder former and an amorphous halo (FIG. 29).

Example 5: Solid Δ⁹-THC Compositions by Rotary Evaporation

A solution of Δ⁹-THC in acetonitrile (1 mL of 50 mg/mL solution, CaymanChemicals) was added to a clean vial. One molar equivalent ofhydroxypropyl-β-cyclodextrin (HPbCD) (248.4 mg, TCI America) was added,producing a slurry. Methanol (3 mL) was added with sonication, and aclear pale yellow solution was observed. The solution was rotaryevaporated (Buchi Rotavapor R-114) with a water bath temperature of 55°C. for approximately 2 minutes. White solids lined the vial, and no oilwas visible. The sample was placed in a vacuum oven at ambienttemperature for 1 day affording a free-flowing, off-white powder thatwas opaque and non-birefringent. The XRPD pattern was obtained for the1:1 Δ⁹-THC/hydroxypropyl-β-cyclodextrin (HPbCD) powder showing amorphoushalos (FIG. 30)

A solution of Δ⁹-THC in acetonitrile (1 mL of 50 mg/mL solution, CaymanChemicals) was added to a clean vial. One molar equivalent oftrimethyl-β-cyclodextrin (TOMBC) (227.4 mg, TCI America) was added,producing a clear solution. The solution was rotary evaporated (BuchiRotavapor R-114) at ambient temperature for approximately 2 minutes, andthe volume was observed to remain consistent. Rotary evaporation wascontinued in a water bath at 32° C., and the sample quickly evaporated,producing white solids. The sample was left on the rotary evaporator forapproximately 4 hours. The resulting white/off-white solids were scrapedand were observed to be glassy. The sample was placed in a vacuum ovenat ambient temperature for 1 day. Upon removal, cracked, glassy,non-birefringent solids were observed. The XRPD pattern was obtained forthe 1:1 Δ⁹-THC/trimethyl-β-cyclodextrin (TOMBC) powder showing amorphoushalos (FIG. 31)

Example 6: Solid Δ⁹-THC Compositions by Lyophilization (Ratio Study)

A commercially available Δ⁹-THC-acetonitrile solution (Cayman Chemical),approximately 50 mg Δ⁹-THC per mL, was used. The actual concentrationwas determined gravimetrically by taring a vial and recording itsweight, adding 1 mL of solution, evaporating the solution, vacuum dryingthe sample at room temperature for 12 hours and reweighing the vial. Theactual concentration was determined to be 51 mg/mL. Into 1 dram vials,300 μl of the Δ⁹-THC acetonitrile solution was dispensed and allowed toevaporate at room temperature resulting in each vial containing ca. 15.3mg of Δ⁹-THC.

Δ⁹-THC (ca. 15.3 mg) was dissolved in dioxane (3 mL solvent used) andtransferred into a 25 mL round bottom flask. The powder former (amountbased on 1:1, 1:2, 1:4, 2:1 or 4:1 molar Δ⁹-THC:powder former ratio) wasdissolved H₂O (2 mL) and, if needed, dioxane (2 mL) was added to form asolution. The powder former solution was added to the Δ⁹-THC solution inthe round bottom flask. The round bottom flask was then submerged in adry ice/acetone bath to freeze the solution while continuously rotatingthe flask by hand to maximize surface area and form an even, thin layeraround the flask. Once frozen, the round bottom flask was attached to aLabConco lyophilizer with an Edwards RV8 vacuum pump pre-equilibrated at˜−50° C. Samples were left overnight (18 hrs) and removed the next day.

Δ⁹-THC and powder formers (aspartame, caffeine and L-valine) werelyophilized using the described procedure to determine if a flowablepowder would result. A sampling of the Δ⁹-THC flowable powders werestored at sub-ambient temperatures (˜−18° C.) for 7 days and observed tosee if a flowable powder remained. A sampling of the Δ⁹-THC flowablepowders were then left at ambient temperature for 7 days and againobserved to see if a flowable powder remained. These results are shownin Table 3.

TABLE 3 Flowable after Flowable after THC: Flowable storage storage atambient PF after at −18° C. temperature Powder former ratiolyophilization (7 days) (7 days) Aspartame 1:1 Yes Yes Yes-Cream color1:2 Yes Yes Yes-Off-white color 1:4 Yes Yes Yes-Off-white color 2:1 YesYes Yes-Cream color 4:1 Yes Yes Yes-Yellow color L-Valine 1:1 Yes YesYes-Off-white color 1:2 Yes Yes Yes-Off-white color 1:4 Yes YesYes-White color 2:1 Yes Yes Yes-Cream color 4:1 Yes Yes Yes-Tan colorCaffeine 1:1 Yes Yes Yes-Tan color 1:2 Yes Yes Yes-Cream color 1:4 YesYes Yes-White color 2:1 No No No-Yellow color 4:1 No No No-Orange browncolor

The flowable powders were characterized using a Rigaku Smart-Lab X-raydiffraction system and their X-ray powder diffraction (XRPD) patternsare shown in FIGS. 32-41.

Example 7: Solid Δ⁹-THC Compositions by Lyophilization (Humidity Study)

A commercially available Δ⁹-THC acetonitrile solution (Cayman Chemical),approximately 50 mg Δ⁹-THC per mL, was used. The actual concentrationwas determined gravimetrically by taring a vial and recording itsweight, adding 1 mL of solution, evaporating the solution, vacuum dryingthe sample at room temperature for 12 hours and reweighing the vial. Theactual concentration was determined to be 51 mg/mL. Into 1-dram vials,1,000 μl of the Δ⁹-THC acetonitrile solution was dispensed and allowedto evaporate at room temperature resulting in each vial containing ca.50 mg of Δ⁹-THC. For each of the following experiments, four 1-dramvials were used totally approximately 200 mg of Δ⁹-THC.

7.1 Scaled Up 1:1 Δ⁹-THC:Aspartame Powder:

Δ⁹-THC (˜200 mg) was dissolved in 1,4-dioxane (8-12 mL of solvent used)and transferred to a 50 mL round bottom flask. In a separate vial,aspartame (1 molar equivalent, 187.3 mg) was dissolved with dioxane andwater. The aspartame solution was added to the LV-THC solution in theround bottom flask. The round bottom flask was then submerged in liquidnitrogen to freeze the solution while continuously rotating the flask byhand in order to maximize surface area and form an even, thin layeraround the flask. Once frozen, the round bottom flask was attached to aLabConco lyophilizer with an Edwards RV8 vacuum pump pre-equilibrated at˜−50° C. The sample was left overnight and removed the next day.

7.2 Scaled Up 1:1 Δ⁹-THC:L-Valine Powder: Δ⁹-THC (˜200 mg) was dissolvedin 1,4-dioxane (8-12 mL of solvent used) and transferred to a 50 mLround bottom flask. In a separate vial, L-valine (1 molar equivalent,74.5 mg) was dissolved with dioxane and water. The valine solution wasadded to the Δ⁹-THC solution in the round bottom flask. The round bottomflask was then submerged in liquid nitrogen to freeze the solution whilecontinuously rotating the flask by hand in order to maximize surfacearea and form an even, thin layer around the flask. Once frozen, theround bottom flask was attached to a LabConco lyophiiizer with anEdwards RV8 vacuum pump pre-equilibrated at ˜−50° C. The sample was leftovernight and removed the next day.

7.3 Scaled Up 1:1 Δ⁹-THC:Caffeine Powder:

Δ⁹-THC (˜200 mg) was dissolved in 1,4-dioxane (8-12 ml of solvent used)and transferred to a 50 mL round bottom flask. In a separate vial,caffeine (1 molar equivalent, 123.4 mg) was dissolved with dioxane andwater. The caffeine solution was added to the Δ⁹-THC solution in theround bottom flask. The round bottom flask was then submerged in liquidnitrogen to freeze the solution while continuously rotating the flask byhand in order to maximize surface area and form an even, thin layeraround the flask. Once frozen, the round bottom flask was attached to aLabConco lyophilizer with an Edwards RV8 vacuum pump pre-equilibrated at˜−50° C. The sample was left overnight and removed the next day.

Each scaled up two-component mixture was then subsampled and stressed atvarious humidity conditions. Materials were visually examined and pouredfor flowability after 1 day, 3 days, 7 days, and 28 days. Humiditystress data of the flowable powders are shown in Table 4.

TABLE 4 Δ⁹-THC: Powder Relative former Humidity Timepoint (1:1 mol:mol)(RH) (days) Observations Aspartame  0% 1 day Flowable, white color 3days Flowable, white color 7 days Flowable, white color 28 daysFlowable, white color 45% 1 day Flowable, white color 3 days Flowable,white color 7 days Flowable, white color 28 days Flowable, white color75% 1 day Flowable, white color 3 days Flowable, white color 7 daysFlowable, white color 28 days Flowable, white color 95% 1 day Flowable,white color 3 days Flowable, white color 7 days Flowable, white color 28days Flowable, white color L-Valine  0% 1 day Flowable, off-white color3 days Flowable, off-white color 7 days Flowable, off-white color 28days Flowable, off-white color 45% 1 day Flowable, off-white color 3days Flowable, off-white color 7 days Flowable, off-white color 28 daysFlowable, off-white color 75% 1 day Flowable, off-white color 3 daysFlowable, off-white color 7 days Flowable, off-white color 28 daysFlowable, off-white color 95% 1 day Flowable, off-white color 3 daysFlowable, off-white color 7 days Flowable, off-white color 28 daysFlowable, off-white color Caffeine  0% 1 day Flowable, cream color 3days Flowable, brown color 7 days Flowable, brown color 28 daysFlowable, dark brown color 45% 1 day Flowable, cream color 3 daysFlowable, cream color 7 days Flowable, cream color 28 days Flowable,cream color 75% 1 day Flowable, cream color 3 days Flowable, orangecolor 7 days Flowable, orange color 28 days Flowable, orange color 95% 1day Flowable, cream color 3 days Flowable, orange color 7 days Tacky,orange color 28 days Tacky, orange color

The claimed invention is:
 1. A solid Δ⁹-THC composition comprisingΔ⁹-THC and aspartame as a powder former and having a molar ratio ofΔ⁹-THC to aspartame powder former to form a flowable Δ⁹-THC powder.
 2. Asolid Δ⁹-THC composition of claim 1 wherein the molar ratio of Δ⁹-THC toaspartame powder former ranges from about 4:1 to about 1:4.
 3. A solidΔ⁹-THC composition of claim 1 wherein the molar ratio of Δ⁹-THC toaspartame powder former ranges from about 3:1 to about 1:3.
 4. A solidΔ⁹-THC composition of claim 1 wherein the molar ratio of Δ⁹-THC toaspartame powder former ranges from about 2:1 to about 1:2.
 5. A solidΔ⁹-THC composition of claim 1 wherein the molar ratio of Δ⁹-THC toaspartame powder former is about 1:1.
 6. A solid Δ⁹-THC composition ofclaim 1 characterized by an X-ray powder diffraction patternsubstantially as shown in FIG. 2, FIG. 21, FIG. 24, FIG. 32, FIG. 33,FIG. 34 or FIG.
 35. 7. A method of making a solid Δ⁹-THC compositioncomprising the step of combining Δ⁹-THC with aspartame as a powderformer under conditions and in a molar ratio to form a flowable Δ⁹-THCpowder.
 8. A method of making a solid Δ⁹-THC composition of claim 7comprising the steps of: dissolving the Δ⁹-THC and the aspartame powderformer in a solvent system to form a solution, and removing the solventfrom the solution to yield a solid Δ⁹-THC composition.
 9. A method ofclaim 7, wherein the dissolving step comprises the steps of: dissolvingthe Δ⁹-THC in a solvent system to form a Δ⁹-THC solution, dissolving theaspartame powder former in a solvent system to form a powder formersolution, combining the Δ⁹-THC solution and the powder former solutionto form a combined solution containing both Δ⁹-THC and the powder formercompound, and removing the solvent from the combined solution to yield asolid Δ⁹-THC composition.
 10. A method of claim 7 wherein the molarratio of Δ⁹-THC to aspartame powder former ranges from about 4:1 toabout 1:4.
 11. A method of claim 7 wherein the molar ratio of Δ⁹-THC toaspartame powder former ranges from about 3:1 to about 1:3.
 12. A methodof claim 7 wherein the molar ratio of Δ⁹-THC to aspartame powder formerranges from about 2:1 to about 1:2.
 13. A method of claim 7 wherein themolar ratio of Δ⁹-THC to aspartame powder former is about 1:1.
 14. Amethod of claim 7 wherein the Δ⁹-THC is synthetic Δ⁹-THC.
 15. A methodof claim 7 wherein the Δ⁹-THC is extracted Δ⁹-THC.
 16. A method of claim8 wherein the solvent is removed from the solution by lyophilization orby evaporation.
 17. A method of claim 9 wherein the solvent is removedfrom the solution by lyophilization or by evaporation.
 18. Apharmaceutical or nutraceutical composition comprising a solid Δ⁹-THCcomposition of claim 1 and a pharmaceutically- ornutraceutically-acceptable carrier, wherein Δ⁹-THC is present in thecomposition in a pharmaceutically or nutraceutically effective amount.19. A method of treating a disease, disorder, or condition comprising:the step of administering to a patient in need thereof a therapeuticallyeffective amount of a solid Δ⁹-THC composition comprising Δ⁹-THC andaspartame as a powder former and having a molar ratio of Δ⁹-THC toaspartame powder former to form a flowable Δ⁹-THC powder, or the step ofadministering to a patient in need thereof a therapeutic compositioncomprising a solid Δ⁹-THC composition a solid Δ⁹-THC compositioncomprising Δ⁹-THC and aspartame as a powder former and having a molarratio of Δ⁹-THC to aspartame powder former to form a flowable Δ⁹-THCpowder and a pharmaceutically- or nutraceutically-acceptable carrier.20. A food or beverage product comprising a solid Δ⁹-THC composition ofclaim 1.